CANCER AND PREVENTION, DIAGNOSIS, AND TREATMENT
The science of treating cancer with specific chemicals as an adjunct to surgery and radiotherapy developed in the second half of the twentieth century, from the use of single agents to the administration of drug cocktails, with spectacular results for some types of cancer. By the beginning of the next millennium, these had been joined by the first ‘targeted’ agents, namely kinase inhibitors and the first monoclonal antibodies. These advances have significantly expanded treatment options but one of the biggest obstacles remains that of drug resistance. The astonishing success of vaccines that prevent infection by human papillomaviruses (HPVs) is already making a major impact on the incidence of cervical carcinoma and other types of cancer caused forms of these viruses.
In parallel with these therapeutic and preventative advances, developments in imaging methods, both for tumour detection and monitoring response to therapy are showing promise. The pressing need to define tumour biomarkers that can be detected at the earliest possible stage has brought the emerging sciences of proteomics and metabolomics to the fore while gene expression profiling has already made substantial contributions to the diagnosis and classification of tumours.
Major developments in surgical methods essentially established the basis for cancer treatment in the early part of the twentieth century. The second half of that century saw the gradual introduction of chemicals for the treatment of disease and the foundation of the science of chemotherapy. In the most general sense chemotherapy means the chemical treatment of disease, something that has been practised since ancient times when the Egyptians used arsenic. However, we are here considering more recent developments, an example being taking penicillin for a bacterial infection that is indeed a course of chemotherapy. In common usage and in the present context the term refers to the use of chemicals to treat cancer, these agents being taken either in combination, with the killing of tumour cells. These cytotoxic drugs are normally administered systemically, meaning that they circulate in the bloodstream and can, in principle, affect every cell in the body. With very few exceptions drugs are not specific, any targeting that may occur arising from, for example, abnormally rapid division rates of tumour cells. However, for the most part, cancer cells proliferate slowly relative to many normal cells and, moreover, their proliferation rates vary widely between different types of a tumour. This problem has an effort on producing toxic agents directed more specifically to tumour cells, either through binding to proteins that are either exclusively, or at least predominantly, present on the surface of tumour cells or by targeting a signalling pathway that to tumour development. The terms hormone therapy, targeted therapy and gene therapy are essentially variants of chemotherapy in which these methods are used to enhance specificity for tumour cells.
One of the earliest demonstrations that chemicals could act as pharmacological inhibitors of cancers came in the early 1940s when Charles Huggins showed that the growth of prostate tumours could be modulated by hormonal treatment. The ensuing 20 years saw the emergence of the antifolate aminopterin, first used by Sidney Farber in 1947, and then of the less toxic methotrexate in 1948 as effective agents against childhood leukaemia. These were followed by 6-thioguanine and 6-mercaptopurine for acute leukaemia and of 5-fluorouracil as the first treatment for solid tumours. It was not until the 1960s, however, that the now common practice of using combinations (cocktails) of drugs was first tested in humans. The results were spectacular in showing that drug combinations could be much more effective than single agents. The use of methotrexate, vincristine, 6-mercaptopurine and prednisone increased the five-year survival rate for childhood acute lymphoblastic leukaemia (ALL) from essentially zero to 60%. By 1996, the development of combination therapy had raised the five-year survival rate to 81%. Currently, children with acute myelogenous leukaemia (AML) have survival rates between 50% and 70%, and over 80% of children with acute promyelocytic leukaemia, a subtype of AML, are cured. By 1980, combination strategies had made similar impacts on Hodgkin’s disease and testicular cancer, which now, provided they are detected at an early stage, have essentially a 100% survival rate.
Nowadays combinations of drugs are often used in a chemotherapy regimen, the idea being to hit different targets in the cancer cell, thereby increasing the ‘fractional kill’ – the proportion of tumour cells eliminated. Chemotherapy regimens are often denoted by acronyms, some of which are fairly logical, e.g. FOLFOX: folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), used to treat bowel cancer; and FOLFIRI: folinic acid, fluorouracil and irinotecan (IRI) (sometimes also with cetuximab) used for colorectal cancer. Others, however, are pretty gnomic (e.g. Stanford V) and it is fortunate that these days one can refer to www.chemocare.com/bio/list_by_acronym.asp for enlightenment.
In the following sections, we will briefly summarise the considerable range strategies that have emerged since the 1980s (Fig. 1) before considering their overall impact on human cancers and how cancer detection and therapy may evolve as we move through the twenty-first century.
1. Potential chemotherapeutic targets for the prevention or inhibition of cancers.
Specific chemical agents mentioned in these sections are only included as examples. A comprehensive table of currently available agents and their cellular targets is given in Appendix B.
We have seen the signs in cancer development of abnormal kinase activities, members of the receptor tyrosine kinase family. Because phosphorylation is such a central mechanism for regulating cell behaviour (there are approximately 518 kinases encoded in the human genome), the kinase family has been the major focus for the design of specific inhibitors. Currently, there are 11 Food and Drug Administration (FDA) approved kinase inhibitors with a further 80 in clinical trials.
Kinases catalyse the removal of the terminal (gamma) phosphate of ATP and its transfer to the amino acids serine, threonine or tyrosine. All kinases have a conserved cleft that contains the binding site for ATP. The majority of kinase inhibitors directly block ATP binding (e.g. PD166326) although those with the greatest selectivity among the kinase family are allosteric inhibitors (e.g. CI-1040). The availability of X-ray crystallographic structures for many kinases has provided a basis for the rational design of inhibitors.
As described previously, the major categories of kinase relevant to cancer are (1) abnormally active as a result of mutation (either within the gene, by amplification or by translocation (e.g. EGFR, ERBB2, BCR-ABL1); (2) key signalling proteins that are rarely mutated but are abnormally activated by upstream regulators (e.g. MEK1/MAP2K1, MEK2/MAP2K2, mTOR); and (3) proteins that support tumour growth, for example, by promoting angiogenesis (e.g. VEGFRs). Food and Drug Administration approved kinase inhibitors include erlotinib (versus EGFR), lapatinib (ERBB2), sorafenib (VEGFRs, PDGFRB and RAF1), sunitinib (VEGFRs, PDGFRB and RET), temsirolimus (mTOR), imatinib (Gleevec® or Glivec®) and nilotinib (BCR-ABL1).
Kinase inhibitors are non-specific in that they cannot distinguish between tumour cells and normal cells, with the exception of imatinib, which targets a mutation in ABL1 (i.e. BCR-ABL1), although it also inhibits KIT and PDGFR. Imatinib has been highly effective, raising the five-year survival rate for chronic myeloid leukaemia (CML) to 89% for newly diagnosed patients in the chronic phase of the disease. It is, however, surprising that the effects of kinase inhibitors on normal cells are sufficiently well tolerated to make them viable therapeutic agents. Some kinase inhibitors have high specificity (e.g. gefitinib for EGFR and imatinib) but, remarkably, some relatively non-specific inhibitors are sufficiently effective to have received FDA approval (e.g. dasatinib for use against CML despite its inhibitory action against members of the SRC family, KIT and PDGFR as well as BCR-ABL1). Dasatinib is a second-generation inhibitor developed to control the expansion of subclones that carry mutations conferring imatinib resistance in patients with CML or gastrointestinal stromal tumours after imatinib treatment. Nevertheless, a relatively common mutation in BCR-ABL1 (at threonine 315) is resistant to all three inhibitors because it locks the molecule in the ABL1-active conformation. New (third-generation) inhibitors targeting the flexible regions involved in the switch between inactive and active conformations are under development. Despite of imatinib in treating CML, it is much less effective against BCR-ABL1-positive ALL. The main reason for this is the presence of deletions of INK4A-ARF in CML. It should also be borne in mind that, in addition to mutations, alternative resistance mechanisms (gene amplification or the up-regulation of alternative kinase pathways) play a substantial part in neutralising the efficacy of kinase inhibitors.
SERMs are selective because some are agonists in all tissues (oestrogen), some are mixed or partial agonists/antagonists in that their effect is tissue dependent (tamoxifen) and some are pure antagonists, acting as such on all tissues (fulvestrant). SERMs are also used in the treatment of osteoporosis.
Monoclonal antibodies are usually considered as a category distinct from conventional chemotherapy drugs. The first monoclonal antibodies for cancer treatment received FDA approval in the late 1990s. These were rituximab (Rituxan®) and trastuzumab (Herceptin®), humanised monoclonal antibodies binding to CD20 and the ERBB2 receptor, respectively. CD20 is a B cell surface protein and rituximab made an immediate impact on the treatment of chemotherapy-resistant forms of non-Hodgkin’s lymphoma and remains in use for B cell lymphomas. Herceptin® is used to treat ERBB2-positive metastatic breast cancer in combination with conventional chemotherapy. Even so, a high proportion of ERBB2+ tumours are unresponsive and drug resistance develops rapidly in responders.
Several other monoclonal antibodies now have FDA approval for cancer use, notably cetuximab (anti-EGFR) for colorectal and head and neck cancers. Monoclonal antibodies have also been used for the targeted delivery of anti-cancer vehicles in (1) radioimmunotherapy (antibodies against cell antigens linked to a radionuclide, so that the target cell is killed by radiation); (2) antibody-directed enzyme prodrug therapy (ADEPT: monoclonal antibodies linked to an enzyme with pro-drug-activating capacity); and (3) immunoliposomes (liposomes being synthetic lipid vesicles that can be formed so that they contain drugs or radionuclides: by incorporating antibodies in the membrane they can be directed to tumour cells). In general, attempts at targeting have been unsuccessful.
The principle of immunotherapy in cancer is to stimulate the activity of the immune system against tumour cells. Two cytokines have FDA approval for use as anti-cancer drugs: interleukin 2 (IL2) and interferon alpha 2b (IFNA2). Interleukins stimulate the proliferation of subsets of T and B cells and interferons to activate particularly natural killer cells and macrophages. IL2 is approved for the treatment of metastatic kidney cancer and metastatic melanoma, although the response rate of melanomas is only about 20%. Interferon alpha is also used for the treatment of melanoma as well as for some leukaemias and AIDS-related Kaposi’s sarcoma. Nonetheless, neither of these is well tolerated, causing side-effects that can include seizures and liver damage.